The quest for genetic risk factors for Crohn's disease in the post-GWAS era

Multiple genome-wide association studies (GWASs) and two large scale meta-analyses have been performed for Crohn's disease and have identified 71 susceptibility loci. These findings have contributed greatly to our current understanding of the disease pathogenesis. Yet, these loci only explain approximately 23% of the disease heritability. One of the future challenges in this post-GWAS era is to identify potential sources of the remaining heritability. Such sources may include common variants with limited effect size, rare variants with higher effect sizes, structural variations, or even more complicated mechanisms such as epistatic, gene-environment and epigenetic interactions. Here, we outline potential sources of this hidden heritability, focusing on Crohn's disease and the currently available data. We also discuss future strategies to determine more about the heritability; these strategies include expanding current GWAS, fine-mapping, whole genome sequencing or exome sequencing, and using family-based approaches. Despite the current limitations, such strategies may help to transfer research achievements into clinical practice and guide the improvement of preventive and therapeutic measures

Meeting of the Ecosystem Approach Correspondence Group on on Pollution Monitoring (CorMon Pollution)

In accordance with the UNEP/MAP Programme of Work adopted by COP 21 for the biennium 2020-2021, the United Nations Environment Programme/Mediterranean Action Plan-Barcelona Convention Secretariat (UNEP/MAP) and its Programme for the Assessment and Control of Marine Pollution in the Mediterranean (MED POL) organized the Meeting of the Ecosystem Approach Correspondence Group on Pollution Monitoring (CorMon on Pollution Monitoring). The Meeting was held via videoconference on 26-27 April 2021. 2. The main objectives of the Meeting were to: a) Review the Monitoring Guidelines/Protocols for IMAP Common Indicator 18, as well as the Monitoring Guidelines/Protocols for Analytical Quality Assurance and Reporting of Monitoring Data for IMAP Common Indicators 13, 14, 17, 18 and 20; b) Take stock of the state of play of inter-laboratory testing and good laboratory practice related to IMAP Ecological Objectives 5 and 9; c) Analyze the proposal for the integration and aggregation rules for IMAP Ecological Objectives 5, 9 and 10 and assessment criteria for contaminants and nutrients; d) Recommend the ways and means to strengthen implementation of IMAP Pollution Cluster towards preparation of the 2023 MED Quality Status Report

Low-Frequency and Rare-Coding Variation Contributes to Multiple Sclerosis Risk

Multiple sclerosis is a complex neurological disease, with 3c20% of risk heritability attributable to common genetic variants, including >230 identified by genome-wide association studies. Multiple strands of evidence suggest that much of the remaining heritability is also due to additive effects of common variants rather than epistasis between these variants or mutations exclusive to individual families. Here, we show in 68,379 cases and controls that up to 5% of this heritability is explained by low-frequency variation in gene coding sequence. We identify four novel genes driving MS risk independently of common-variant signals, highlighting key pathogenic roles for regulatory T cell homeostasis and regulation, IFN\u3b3 biology, and NF\u3baB signaling. As low-frequency variants do not show substantial linkage disequilibrium with other variants, and as coding variants are more interpretable and experimentally tractable than non-coding variation, our discoveries constitute a rich resource for dissecting the pathobiology of MS. In a large multi-cohort study, unexplained heritability for multiple sclerosis is detected in low-frequency coding variants that are missed by GWAS analyses, further underscoring the role of immune genes in MS pathology

Limited Evidence for Parent-of-Origin Effects in Inflammatory Bowel Disease Associated Loci

Background: Genome-wide association studies of two main forms of inflammatory bowel diseases (IBD), Crohn's disease (CD) and ulcerative colitis (UC), have identified 99 susceptibility loci, but these explain only similar to 23% of the genetic risk. Part of the 'hidden heritability' could be in transmissible genetic effects in which mRNA expression in the offspring depends on the parental origin of the allele (genomic imprinting), since children whose mothers have CD are more often affected than children with affected fathers. We analyzed parent-of-origin (POO) effects in Dutch and Indian cohorts of IBD patients. Methods: We selected 28 genetic loci associated with both CD and UC, and tested them for POO effects in 181 Dutch IBD case-parent trios. Three susceptibility variants in NOD2 were tested in 111 CD trios and a significant finding was re-evaluated in 598 German trios. The UC-associated gene, BTNL2, reportedly imprinted, was tested in 70 Dutch UC trios. Finally, we used 62 independent Indian UC trios to test POO effects of five established Indian UC risk loci. Results: We identified POO effects for NOD2 (L1007fs; OR = 21.0, P-value = 0.013) for CD; these results could not be replicated in an independent cohort (OR = 0.97, P-value = 0.95). A POO effect in IBD was observed for IL12B (OR = 3.2, P-value = 0.019) and PRDM1 (OR = 5.6, P-value = 0.04). In the Indian trios the IL10 locus showed a POO effect (OR = 0.2, P-value = 0.03). Conclusions: Little is known about the effect of genomic imprinting in complex diseases such as IBD. We present limited evidence for POO effects for the tested IBD loci. POO effects explain part of the hidden heritability for complex genetic diseases but need to be investigated further

Phenotypic characterization of subjects with Crohn’s disease.

<p>Phenotypic characterization of subjects with Crohn’s disease.</p

Phenotypic characterization of subjects with ulcerative colitis.

<p>N/A not available, AOO average age of onset. Cases and disease location are given according to the Montreal classification. for CD L1, L2, L3 and L4; for UC E1, E2, E3. No phenotypic information was available for the German cohort.</p

Results of the parent-of-origin (POO) analysis in the BTNL2 locus in Dutch UC ulcerative colitis trios (n = 72).

<p>P-value (p-α; ß; γ) and odds ratio (OR-α; ß; γ) of the alpha-, beta-, and gamma-term. Alpha-term indicates the genomic imprinting effect; Beta-term and gamma-term indicate the maternal effect in case the mother carries respectively two and one risk alleles. Significant associations are in bold. P-values displayed in the table are not corrected for multiple testing.</p